Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy.

TitleSingle cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy.
Publication TypeJournal Article
Year of Publication2020
AuthorsWisdom, Amy J., Yvonne M. Mowery, Cierra S. Hong, Jonathon E. Himes, Barzin Y. Nabet, Xiaodi Qin, Dadong Zhang, Lan Chen, Hélène Fradin, Rutulkumar Patel, Alex M. Bassil, Eric S. Muise, Daniel A. King, Eric S. Xu, David J. Carpenter, Collin L. Kent, Kimberly S. Smythe, Nerissa T. Williams, Lixia Luo, Yan Ma, Ash A. Alizadeh, Kouros Owzar, Maximilian Diehn, Todd Bradley, and David G. Kirsch
JournalNat Commun
Volume11
Issue1
Pagination6410
Date Published2020 Dec 17
ISSN2041-1723
KeywordsAnimals, Antineoplastic Agents, Immunological, Bone Marrow Transplantation, CD8-Positive T-Lymphocytes, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Immunotherapy, Mice, Inbred Strains, Programmed Cell Death 1 Receptor, Sarcoma, Single-Cell Analysis, Tumor Escape, Tumor Microenvironment, Whole Exome Sequencing
Abstract

Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.

DOI10.1038/s41467-020-19917-0
Alternate JournalNat Commun
Original PublicationSingle cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy.
PubMed ID33335088
PubMed Central IDPMC7746723
Grant ListR38 CA245204 / CA / NCI NIH HHS / United States
R35 CA197616 / CA / NCI NIH HHS / United States
U24 CA220245 / CA / NCI NIH HHS / United States
P30 CA016086 / CA / NCI NIH HHS / United States
U54 CA168512 / CA / NCI NIH HHS / United States
R01 CA233975 / CA / NCI NIH HHS / United States
P01 CA142538 / CA / NCI NIH HHS / United States
F30 CA221268 / CA / NCI NIH HHS / United States